目的 在“聚于胃，关于肺”视角下探索胃食管反流病（gastroesophageal reflux，GERD）与特发性肺纤维化（idiopathic pulmonary fibrosis，IPF）共病“中虚气逆”病机的生物学内涵，并探索麦门冬汤干预共病的机制。方法 从基因表达综合数据库获取GERD和IPF基因表达谱以筛选共享差异表达基因（differentially expressed genes，DEGs），免疫细胞浸润与基因集富集分析（gene set enrichment analysis，GSEA）鉴定共病核心生物通路以揭示GERD与IPF共病的生物学机制。综合网络药理学、分子对接、受试者操作特征（receiver operating characteristic，ROC）曲线、外部数据集验证和功能富集分析探索麦门冬汤干预共病的核心靶点及机制。从Decode获取血浆顺式蛋白质数量性状位点数据，从IEU OpenGWAS获取GERD和IPF的全基因组关联研究数据，利用孟德尔随机化（mendelian randomization，MR）验证麦门冬汤干预共病的核心靶点。结果 共得到1 303个共享DEGs；静息树突状细胞、M0期巨噬细胞、浆细胞和调节性T细胞在GERD与IPF中表达趋势相同；共病核心生物通路包括凝固、上皮间质转化、鼠类肉瘤病毒癌基因（kirsten rat sarcoma viral oncogene，KRAS）通路下调和血管生成等。209个麦门冬汤有效成分作用于16个共病靶点，这些靶点主要富集在晚期糖基化终末产物及其受体、细胞周期、血小板活化等通路。分子对接、ROC曲线、外部数据集和MR明确了3个共病核心靶点：III型胶原蛋白的α1链［collagen alpha-1 (III) chain，COL3A1］、组织蛋白酶K（cathepsin K，CTSK）和半乳糖凝集素（galectin-7，LGALS7）。其中COL3A1与GERD和IPF发病呈负相关，LGALS7与GERD和IPF发病呈正相关，CTSK与IPF发病呈负相关、与GERD发病呈正相关。结论 促炎与抗炎免疫细胞失衡是GERD与IPF共病“中虚气逆”病机的生物学内涵，麦门冬汤可以通过调控免疫炎症等途径干预共病，丰富了“聚于胃，关于肺”理论的内涵，为共病机制及干预研究提供了参考。

Objective To explore the biological connotation of “Zhongqi deficiency inverse” in gastroesophageal reflux disease (GERD) and idiopathic pulmonary fibrosis (IPF) comorbidity from the perspective of “gathering in the stomach, focusing on the lung”. Moreover, it explores the mechanism of Maimendong Decoction (麦门冬汤) in the multimorbidity intervention. Methods GERD and IPF gene expression profiles were obtained from the Gene Expression Omnibus database to screen shared differentially expressed genes (DEGs). Gene set enrichment analysis (GSEA) and immune cell infiltration identified core biological pathways to reveal the biological mechanism of GERD and IPF comorbidity. Network pharmacology, molecular docking, receiver operating characteristic (ROC) curve, external dataset validation and functional enrichment analysis were used to explore the core targets and mechanisms of Maimendong Decoction in the intervention of multimorbidity. The quantitative trait loci of plasma cis proteins were obtained from Decode, and the genome-wide association study data of GERD and IPF were obtained from IEU OpenGWAS. Mendelian randomization (MR) was used to verify the core targets of Maimendong Decoction in the intervention of comorbidities. Results A total of 1 303 shared DEGs were obtained. The expressions of resting dendritic cells, M0 phase macrophages, plasma cells, and regulatory T cells in GERD and IPF were similar. The core biological pathways of comorbidity include coagulation, epithelial-mesenchymal transition, downregulation of the kirsten rat sarcoma viral oncogene (KRAS) pathway, and angiogenesis. A total of 209 active components of Maimendong Decoction acted on 16 comorbidity targets, which were mainly enriched in advanced glycation end products and their receptors, cell cycle, platelet activation, and other pathways. Molecular docking, ROC curves, external datasets, and MR identified three core targets for comorbidity: collagen alpha-1 (III) chain was negatively correlated with GERD and IPF, galectin-7 was positively correlated with GERD and IPF, and cathepsin K was negatively correlated with IPF and positively correlated with GERD. Conclusion The imbalance of pro-inflammatory and anti-inflammatory immune cells is the biological connotation of the comorbidity of “Zhongqi deficiency inverse” in GERD and IPF. Maimendong Decoction can intervene with the comorbidity by regulating immune inflammation and other mechanisms, which enriches the connotation of the theory of “gathering in the stomach, focusing on the lung” and provides a reference for the study of the mechanism and intervention of the comorbidity.

Q811.4;TP18;R285

国家自然科学基金面上项目（82174347，82374403）；四川省中医药管理局面上项目（2023MS363）；成都中医药大学2023年度“杏林学者”学科人才青基进阶人才专项（QJJJ2023006）